Function _'s treatment method in the liver is damaged of nitrous oxides

Function _'s treatment method in the liver is damaged of nitrous oxides
Function in the liver is damaged of nitrous oxides

Chinese infectious disease magazine Vol. 16 of number 1 of 1998 Survey

Author: Xing HuiChun Wang ShouYi

Unit: 030001 Taiyuan, the first hospital of mountain Western medicine university

Nitrous oxides (nitricoxide, NO) It is a kind of internal essential information molecules, has malicious function of cell. When causing the son of cause of disease to attack the liver, the endotoxin can cause the cover in the liver or blood vessel to produce a large amount of NO, participate in its physiological course of pathology.

First, NO induction in the liver are formated

There is a large amount of NO that emerges in patient's body of disease and shock of endotoxic blood, reveals the big mouse's hepatocyte (HC) of this disease with Northern blot There is inducing NO synthase (inducible nitric oxide synthase, iNOS) inside MRNA express to increase,blood plasma at the same time Central Asia nitrate (NO-2)With nitrate (NO-3)(the steady end product of NO supersession) Increase[1]. In endotoxic lipopolysaccharide (LPS) of bacterium The liver of mouse that defies in advance leaves the body and irritates and flows NO in liquid-2/NO-3Produce and obviously increase, use L - single methyl arginine (NG-Monomethyl-L-arginine, L-NMMA, a kind of NO synthase inhibitor) Can inhibit most NO-2/NO-3Produce, this indicate liver have L - arginine - the intersection of NO and supersession that LPS stimulate[2]. External experiment in withered to deny cell (KC) Train and join LPS in the liquid, can produce a large amount of NO. Hepatocyte with withered to deny cell train together and in have withered deny clear liquid at the whom cell train or have many kinds of cell factors, can be stimulated by LPS to produce a large amount of NO. Ito cell can also receive LPS and - interferon (IFN - ) , tumour necrosis factor (TNF - ) Wait for function and express iNOS, and formate a large amount of NO[3].

NO can also induce and formate in the blood vessel. Someone finds that there is activation of iNOS in the blood vessel of the liver cirrhosis mouse. It can make structural nitrous oxides synthase in endothelial cells excessive and express that also the evidence shows endotoxin, beating blood flow, turns into the stress, NO formates and increases. Smooth cells can also be induced to by the above-mentioned factor formate a large amount of NO.

It is not so obvious that it is machine-processed that LPS causes iNOS to express. According to thinking the nuclear factor KB plays a key role among them, employ Pentamethyle-hydroxychromance (inhibitor of a kind of NFKB) Can inhibit the expression of this gene[4].

Second, impact on NO production of cell factor

LPS initiates internal NO to formate and increase, LPS can cause macrophages, KC,etc. produces many kinds of cell factors, and factor of these cells participates in NO synthetic regulation conversely.

TNF - is considered to be a synthetic important person who regulates of NO. Participating in hepatocyte, smooth muscle cell and endothelial cell, the induction of NO is formated. When the endotoxin causes little mouse's liver to damage, blood plasma NO-2/NO-3Accompany by the one TNF increased. If resist mouse - TNF - to resist more with the rabbit in advance, can make TNF - 's level in the blood obviously reduce, NO at the same time-2/NO-3The density is also reduced[5]. Other cell factors also participate in NO synthetic regulation. Isolate liver, train outside the cell body from big mouse that LPS defy in advance, join TNF - or IL-1 can make iNOS mDNA express in the hepatocyte[1]. IFN - can make, come from endotoxic the intersection of blood and the intersection of disease and cell, Ito of mouse, formate NO increase[3]. Though IL-6 fails to make the hepatocyte express iNOS mRNA alone, can make this kind of effect of IL-1 obviously increase[1]. TNF - and IL-1 , TNF - and IFN - demonstrate the obvious cooperative effect. Another some the intersection of cell and to to produce, shoulder to regulating action while being synthetic NO factor. Growth factor - is duplicated through inhibiting iNOS such as transforming, reduce iNOS mRNA stability, promotes the resolving of iNOS albumen and inhibits the biosynthesis of NO. In addition IL-4, IL-8, IL-10 and PGE2Reduce NO synthetic function.

The cell factor can also be through regulating influencing the formation of NO synthetically of other cell factors, form a complicated network system.

Third, NO role in liver disease

Ma does not irritate while flowing until ischemic in the liver, finds liver free radical increases. If loud mouse deals with LPS first, although increased NO can be totally removed because of irritating free radicals produced again, but AST raises, can prevent this kind of effect due to LPS with L-NMMA, points out NO and perhaps reacts with the peroxide, participate in the damage course of the liver together[2]. NO toxic effect in the liver mainly shows:

1. NO inhibits mitochondria from breathing the chain. According to think NO that macrophage produce it wounds mechanisms of effect one of to be to inhibit mitochondria from breathing the chain to microorganism and the intersection of tumour and cell, have hindered the formulation of energy. Train HC in the liquid to join other source NO, the compound thing of mitochondrial aconitase and mitochondrial electron transfer chain on reliance of density (complement enzyme and take off hydrogen appears promptly 5 minutes later And complex 2 (amber sour desaturase) Active inhibition, in 6 hours after withdraw from NO, the active full restoration of mitochondrial aconitase. Compound the thing activity to also resume partly. L-NMMA can reverse the inhibition that NO breathed to mitochondria of hepatocyte partially. But NO has not almost influenced the compound thing, compounding things of aconitase and mitochondrial electron transfer chain in the liquid of afterbirth. Indicate the inhibition that NO breathes to mitochondria has an alternative one, and the most sensitive one is mitochondrial aconitase. This may because enzyme to store position in to be different. Aconitase presents and dissolves the state in the liquid of afterbirth, but bind in mitochondria with inner membrane, make and kissing the lipoprotein NO is apter to combine[6].

2. NO inhibits the hepatocyte albumen from formating. Hepatocyte that train act on LPS or some the intersection of cell and factor, can make, train NO in the liquid outside the body-2/NO-3Increase, with the synthetic reducing of total albumen at the same time; Exposed to the albumen that other source NO can also produce density reliance to formate and inhibit. This kind of inhibitory activity can be prevented by L-NMMA, if add L - arginine and reappear again again, indicate NO formates inhibitory activity to the albumen[7]. But Frederick,etc. is while finding big mouse's endotoxic blood disease in the whole experiment, the increase that is formed along with NO is that HC formates the increase of the albumen. This author is regarded as because NO promotes the function of the blood flow of liver to offset NO synthetic direct inhibitory activity to hepatocyte albumen. Also train NO density in the liquid with the internal NO density than external cells low and relevantly. Plasma protein and a kind of reason that the blood coagulation factor drops when NO synthetic inhibition to albumen may be chronic hepatopathy.

3. NO inhibition of other supersession. NO has influence on that hepatocyte glucose is formated. Horton is 3 hours after dealing with the big mouse with LPS, iNOS increases, correlates with synthetic inhibition of hepatocyte glucose that is isolated subsequently in the hepatocyte. Stadler,etc. trains HC and IFN - , IL-1 , TNF - and LPS together, inducible NO formates, the glucose output is reduced by 48.8% at the same time, can totally reverse this effect with L-NMMA. Other source NO can cause the synthetic inhibition of hepatocyte glucose on reliance of the density too[8]. This foundation that blood glucose reduces when being may be hepatopathy or suppuration and poisonous blood disease. Have materials show NO, can stimulate the intersection of liver and production of glucose temporarily also.

NO can inhibit it from formating through inhibiting DNA synthetic enzyme[3],Also can make inferior the intersection of nitre and acyl it through bind with DNA, cause the intersection of DNA and rupture or sudden change, influence his supersession, in addition NO also has influence on the lipoprotein supersession.

The mechanism on the toxic effect of liver of NO has not been totally distinct, NO contains an electron in pairs, act on other electrons in pairs with materials such as the inferior iron ion, sulfhydryl- base,etc., it may be a foundation on its function to make its function damage. In addition NO can also be with O-2The response produces and exceeds and oxidizes the inferior nitric acid anion (ONOO-)And other free radicals cause lipid to cross and oxidize, function enzyme, structural albumen,etc. are destroyed.

Cell exposed to high-level NO, reveal, damage effect continuously, have evidence indicate NO have protective action to the liver also. Billiar,etc. causes little mouse's liver to damage with LPS, NO formates and increases. Although NO synthase inhibitor can reduce the production of NO prominently, the liver is damaged and obviously aggravated. The endotoxic blood disease patient obviously rises with bilirubin of blood and ALT after L-NMMA. Indicate NO in swollen to lie between, lead liver, damage while being dirty, shield, host to essential response that inflammation react[5]. NO is not so obvious to the mechanism on the protective action of liver, someone thinks LPS causes the liver to be damaged and may be lain between and led of reactive oxygen mediumed, NO can react and produce the low toxic material as a kind of antioxidant but and ultra oxygen anion or other free radicals, until microscope observe change that liver a little circulates under the little the intersection of mouse and endotoxic the intersection of blood and disease in the living subject Nishida,etc., find, share the intersection of NO and synthase behind the inhibitor, liver the leucocyte is adhered to 5- 6 times higher than the control group in the sinus, see the sinus diameter shrink at the same time, the sinus blood flow volume of liver is reduced, cover swelling in the sinus, the blood platelet assembles. If circulate a little disorderlily this kind that L - arginine can dispel the liver at the same time, indicate NO can regulate the liver to circulate in endotoxic blood disease a little. The ones that prevent the liver and result from the reason that ischemic or the leucocyte is adhered to are oxidized and damaging[10]. But Stadler thinks under some inflammatory states, the liver function obstacle is because of the inhibition of the cellular metabolism of liver, it is not irritating and flowing the question of liver.

Forming that high motive force circulated when NO still participates in liver cirrhosis. With react, park, inhibit experimental the intersection of door and the intersection of pulse and high-pressure NO of mouse from produce Lopez-Talavera,etc. ,Can improve average arterial pressure and blood vessel resistance of the systemic circulation, reduce the pulse pressure of the door notably[11]. This may be that NO that the cover produces acts on sour ring enzyme of glucoside of bird in the smooth muscle cells of blood vessel in the blood vessel, make cGMP formate and increase, calcium ion is released on the cytoplasm, enable smooth muscle cell relaxation in the skin thick liquid network, angiectasis. And around blood vessel it expands to be the intersection of liver cirrhosis and the intersection of door and the intersection of pulse and high-pressure the intersection of sodium and water retention, ascites form and the intersection of liver and the intersection of kidney and whom syndrome produce start to move the factor.

Fourth, understanding of NO double action

In sum, NO is shown as two kinds of contradictory effects each other in liver disease. Support the training for external cells more of malicious function of NO cell, the influence factor is relatively single, and NO density is much higher than vivo experimentation; NO protective action reveal in the experiment of the integral level or organ level more, the function of other cells factor participation that may be had in succession or followed, the influence factor is relatively complicated. The environment that natural cells live in the body is not also the same. Ma,etc. thinks that expands pharmaceuticals to resist ischemic and shieldingly as the blood vessel in physiological function of NO; Its chemical property is free radical, can form the toxic material. This kind of double action may depend on organizing and physiological environment. When organizing oxygen to be poor, increased NO may mainly play a expanding the blood vessel role, inhibit the leucocyte to adhere to and assemble, organize irritating and flowing and lightening and damaging by increasing; When organizing oxygen to be competent, perhaps NO reacts, has dispelled expanding the function of blood vessel of NO with the peroxide, produce directly toxic materials (ONOO at the same time-). It expands function of blood vessel, because of in different courses of disease or acting on different positions to also show as different effects. When the liver liver is damaged, NO can shield through improving the blood flow of liver, but NO participates in the pathologic course that its high motive force circulates in liver cirrhosis. Billiar,etc. thinks ONOO-While there are not plasma protein and glutathion, can cause the blood platelet to assemble and damage, but under the physiological environment, prevent the blood platelet from assembling. According to thinking NO and O-2Ratio last lipid to last their toxicity's decisive factors to react.

References

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